Effects of cannabidiol in chronic non-cancer pain on chronic opioid therapy

项目小结 越来越多的证据表明内源性大麻素系统在神经调节中起作用 参与阿片类药物使用/成瘾和疼痛的过程。对人类的临床前和初步研究表明 大麻二醇(CBD)可能有助于CNCP患者减少阿片类药物的使用和减轻疼痛 症状，但还没有关于CBD对人类的影响的研究，CNCP维持在 小床。这项双盲、安慰剂对照、概念验证试验旨在比较口服 40例CNCP综合征(无OUD共发)门诊患者给予CBD 600 mg安慰剂，维持 稳定的中到高剂量阿片类止痛药至少3个月，并有动力减少其 阿片类止痛剂维持量。试验期为6个月，并将包括4个月的治疗 每日服用CBD 600 mg与安慰剂对照，然后停药2个月(随机化) 药物或安慰剂。CBD的安全性和耐受性将在整个试验过程中进行评估。阿片类止痛药 维持剂量和疼痛将在基线和纵向进行评估。几种势能的变化 将测量治疗效果的中介因素(阿片类药物维持剂量的变化)(在基线和 纵向)包括：痛苦、心理领域(抑郁、焦虑、睡眠)、改变的动机 阿片类药物维持用药剂量和阿片类药物滥用/成瘾的标志(如渴求、戒断 症状)。对于患有CNCP的门诊患者，将在常规治疗(即COT)的基础上实施CBD 综合症。这将是探索CBD对CNCP综合征患者影响的第一项临床试验 (没有OUD，但有发展OUD的风险)，在胶床上维护，并评估其安全性 使用阿片类镇痛剂。这项拟议的研究在使用CBD治疗阿片类药物方面具有很高的创新性 在COT上CNCP患者中使用DOMAIN，试图减少与 中至高剂量胶床。此外，它是创新的，因为CBD的行动机制是 不同于目前用于治疗疼痛的药物，也不同于用于治疗 可能会影响阿片类药物滥用/成瘾的基本神经生物学，包括减少中毒， 戒断、线索诱导的渴求和寻求毒品的行为、压力反应和冲动。动物 人体试验表明，持续的疾病修正变化可能会因此发生 CBD的治疗持续时间相对较短，这将代表一种使用 预防COT上CNCP中OUD的药物干预具有临床意义的论证 中到高剂量COT治疗CNCP患者减少阿片类药物的使用和疼痛可能有 在减少不良后果(即阿片成瘾和过量死亡)和改善 生活质量，以及慢性神经生物学基础知识的交集 疼痛和阿片类药物的使用/滥用。

Project Brief Summary There is growing evidence implicating the endogenous cannabinoid system in mediating neural processes involved in opioid use/addiction and pain. Preclinical and preliminary studies in humans suggest that cannabidiol (CBD) may be helpful in reducing opioid use and decreasing pain in patients with CNCP syndromes but no studies have yet been conducted of the effects of CBD in humans with CNCP maintained on COT. This double-blind, placebo-controlled, proof-of-concept trial is designed to compare effects of oral CBD 600mg to placebo in 40 outpatients with CNCP syndromes (without co-occurring OUD), maintained on stable moderate to high-dose opioid analgesics for a minimum of 3-months, and motivated to decrease their opioid analgesic maintenance dose. The trial duration will be 6-months and will include a 4-month treatment period (following randomization) of daily CBD 600mg vs placebo, followed by 2 months off of study medication or placebo. Safety and tolerability of CBD will be assessed throughout the trial. Opioid analgesic maintenance dose and pain will be assessed at baseline and longitudinally. Changes in several potential mediators of treatment effect (change in opioid maintenance dose) will be measured (at baseline and longitudinally) including: pain, psychological domains (depression, anxiety, sleep), motivation to change dose of opioid maintenance medication, and markers of opioid misuse/addiction (i.e. craving, withdrawal symptoms). CBD will be administered on top of treatment as usual (i.e. COT) for outpatients with CNCP syndromes. This would be the first clinical trial exploring the effects of CBD in patients with CNCP syndromes (without OUD but at risk for developing an OUD), maintained on COT, and to assess its safety when co- administered with opioid analgesics. The proposed study is highly innovative in using CBD to treat the opioid use domain in patients with CNCP on COT, in an attempt to reduce the potential harms associated with moderate to high-dose COT. Further, it is innovative because CBD has mechanisms of action that are different from medications currently used in the treatment of pain, and also in the treatment of OUDs which could affect the basic neurobiology of opioid misuse/addiction including reductions in intoxication, withdrawal, cue-induced craving and drug seeking behaviors, stress responsivity, and impulsivity. Animal and human trials suggest the possibility that sustained disease-modifying changes could occur as a result of relatively brief treatment duration with CBD, which would represent a novel approach in using a pharmacologic intervention to prevent OUD in CNCP on COT. Demonstration of clinically meaningful reductions in opioid use and pain in patients with CNCP on moderate to high-dose COT could have an enormous impact in reducing adverse outcomes (i.e. opioid addiction and overdose fatalities) and improving quality of life, as well as advancing knowledge of the neurobiological basis of the intersection between chronic pain and opioid use/misuse.